1. Study of cognitive functions a. fMRI Studies of Socioemotional Processing. The purpose of this study is in part to examine differences in socioemotional processing related to AUD. We have conducted and presented interim analyses at scientific conferences. We found that Individuals with AUD compared to controls engaged in response inhibition via engagement of the ventral anterior cingulate and memory recall via engagement of the hippocampus during presentation of alcohol distractors alongside socioemotional stimuli. Similar effects were seen in the orbitofrontal cortex. Individuals with AUD had less engagement in moral processing regions (posterior cingulate, temporoparietal junction, and frontal pole) during presentation of alcohol distractors alongside moral stimuli. Similar effects seen in amygdala, medial prefrontal cortex, and temporal pole regions. These effects are more pronounced in individuals with greater alcohol consumption. These results suggest that alcohol cues interfere in cognitive and affective processing. b. Differences in discounting rates and neural processes involved in decision making between heavy drinkers vs. light drinkers will be tested in an upcoming study. This study will help understand these differences when the immediate and future reward involve either alcohol or money, and when these reward cues are presented in the context of negative and positive consequence stimuli. The results from this study may provide information regarding potential treatment targets for individuals with AUD to make less impulsive choices using approaches such as neurofeedback or transcranial magnetic stimulation persons. c. The interaction of cognitive and motor processes in alcoholics is currently being assessed using the inhibitory interference of response task (IIRT). This study will test this interaction by assessing the behavioral and neural response related to the inhibitory response in alcoholics and how it compares to healthy control participants. d. We are determining and studying neural correlates of decision making when making choices about whether to give money to charitable causes. Previous studies find that charitable decision making is associated with integration of value computing (from the ventral striatum) with social cognitive processing (such as in the insula and temporoparietal junction) through the ventromedial prefrontal cortex (vmPFC; e.g., Hare et al., 2010; Izuma et al., 2010; Tusche et al., 2016). The above mentioned regions have been implicated in AUD and our goal in conducting this study is whether such an fMRI task would provide further granularity in the decision making process of AUD patients as a biomarker. 2. fMRI Studies of Motivation a. In collaboration with Dr. Falk Lohoffs Section on Clinical Genomics and Experimental Therapeutics (CGET), we analyzed Monetary Incentive Delay (MID) task data to investigate if there were any association between a number of genetic variants implicated in psychiatric disorders the and activation in dorsal striatum during reward processing in patients with alcohol use disorder (AUD). i. Common MDD and AUD risk variant. AUD is often comorbid with other psychiatric disorders such as major depressive disorder (MDD). A locus in the TMEM161B-MEF2C region (rs10514299) has been identified as a risk variant for MDD. On the other hand, previous reports have shown the disruption of reward processing in both AD and MDD. We examined the association between rs10514299 and striatal BOLD responses during reward/loss anticipation in AUD. Patients carrying the T allele showed significantly greater putamen activation during anticipation of high reward and loss (high and low) avoidance, and a trend towards anticipation of low reward compared to healthy controls, HCs. (Muench et aL 2018) ii. Genetic Variation in COMT predicts reward processing in AUD. We have also collaborated with Dr. Lohoffs group to determine whether genetic variation in COMT in individuals with AUD and HCs is associated with differential striatal (caudate, putamen, nucleus accumbens) BOLD responses during reward processing. In this study, patients with AUD had showed significantly greater activation in regions of the ventral striatum during reward anticipation compared to controls. The AUD group also showed significantly greater activation in the caudate and nucleus accumbens during loss avoidance anticipation. Individuals with AUD who carry the minor T-allele showed significantly greater BOLD responses during reward anticipation compared to controls. This response was in opposite direction for the HCs. This finding points to the possibility using reward anticipation response as a biomarker of AUD in this variant of COMT gene. (Muench et al., 2018) b. Compulsivity and Reward Incentive Delay with Shock (RIDs) Task. We have conducted a novel translational study to explore the neural correlates of aversion resistant alcohol addiction using a paradigm, which adds an aversive component to the RID task. In this study, the participants (light and heavy drinkers) were able to earn points for real alcohol and food rewards at the risk of receiving a small electric shock. Compared with light drinkers, heavy drinkers attempted to earn more aversion-paired alcohol points. Fronto-striatal circuitry, including the medial prefrontal cortex, anterior insula, and striatum, was more active in this group when viewing threat-predictive alcohol cues. Heavy drinkers had increased connectivity between the anterior insula and the nucleus accumbens. Greater connectivity was associated with more attempts to earn aversion-paired alcohol points and self-reported compulsive alcohol use scores. Higher activation of fronto-striatal circuitry in heavy drinkers may be associated with compulsive alcohol seeking (Grodin et al., 2018). We are currently revising the follow up study that would compare the above results with a more general salient reward such as money in heavy alcohol drinkers in contrast to light drinkers. This study has the potential of unravelling whether the failure to avoid actions with negative consequences are specific to alcohol or in general to any reward. 3. fMRI Studies of Stress In a collaborative study with Dr. Lohoffs CGET we have implemented an fMRI fear extinction task. The primary goal of this study is to evaluate the role and interaction of (epi)genetic factors, early life stress (ELS) exposure, and alcohol use disorder (AUD) on neuronal mechanisms of fear conditioning and extinction. This cross-sectional, case-control study found significantly reduced amygdala activation during fear conditioning and fear renewal in individuals with alcohol dependence compared to healthy controls. Decreased amygdala activation during fear conditioning was significantly associated with alcohol dependence-related clinical measures, including alcohol dependence severity, depressive symptoms, trait anxiety, and perceived stress. (Muench et al., 2019, submitted) 4. Experimental fMRI Studies and Treatments a. Effect of Pioglitazone on reward response in patients with alcoholism. We have evaluated the role of pioglitazone, an anti-inflammatory drug, on the neural processes associated with craving related reward response in a monetary incentive delay task. This study was done in collaboration with Dr. Nancy Diazgranados. The effects were studied in inpatients that received the pioglitazone treatment and a control group of inpatients that received a placebo. The grouping was double blinded and randomly assigned. The placebo group showed significantly greater activation in the posterior cingulate area during the anticipation phase, and activation in the precuneus, sensory motor area and precentral gyrus during reward specific anticipation compared to the treatment group. (Data presented at 2019 RSA conference)